Aminothienopyridazines as imaging probes of tau pathology: a patent evaluation of WO2013090497

Small-molecule ligands, amenable to positron emission tomography (PET) imaging of different types of neurodegenerative disease-associated amyloid deposits in the CNS of living patients, hold considerable promise for diagnostic purposes, as well as for monitoring disease progression and the effectiveness of treatments. The patent entitled ‘Heterocyclic Compounds as Imaging Probes of Tau Pathology' (WO2013090497) discloses the identification of a novel class of tau imaging agents, the aminothienopyridazines. Selected compounds from this class are described that can stain selectively tau pathology in brain tissue sections. Moreover, examples of this class of compounds exhibit absorption, distribution, metabolism, excretion and pharmacokinetics (ADME-PK) properties that are appropriate for CNS PET ligands.

[1]  H. Kolb,et al.  [18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease , 2013, Alzheimer's & Dementia.

[2]  J. Trojanowski,et al.  Imaging of Tau Pathology in a Tauopathy Mouse Model and in Alzheimer Patients Compared to Normal Controls , 2013, Neuron.

[3]  H. Arai,et al.  Novel 18F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease , 2013, The Journal of Nuclear Medicine.

[4]  L. Chen,et al.  Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligand. , 2013, Journal of medicinal chemistry.

[5]  J. Trojanowski,et al.  Aminothienopyridazines and Methylene Blue Affect Tau Fibrillization via Cysteine Oxidation* , 2013, The Journal of Biological Chemistry.

[6]  E. Mandelkow,et al.  Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity. , 2012, Human molecular genetics.

[7]  J. Trojanowski,et al.  Aminothienopyridazine inhibitors of tau aggregation: evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties. , 2012, Bioorganic & medicinal chemistry.

[8]  J. Trojanowski,et al.  Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation. , 2010, Journal of medicinal chemistry.

[9]  Ruili Huang,et al.  Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. , 2009, Biochemistry.

[10]  P. Sexton,et al.  2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists. , 2008, Journal of medicinal chemistry.

[11]  H. Arai,et al.  Recent advances in the development of amyloid imaging agents. , 2007, Current topics in medicinal chemistry.

[12]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.

[13]  Chester A. Mathis,et al.  A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. , 2002, Bioorganic & medicinal chemistry letters.

[14]  W. Klunk,et al.  Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. , 2001, Life sciences.

[15]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[16]  G. K. Wilcock,et al.  Plaques, tangles and dementia A quantitative study , 1982, Journal of the Neurological Sciences.

[17]  K. Gewald.  Heterocyclen aus CH‐aciden Nitrilen, VII. 2‐Amino‐thiophene aus α‐Oxo‐mercaptanen und methylenaktiven Nitrilen , 1965 .

[18]  Min-Ying Su,et al.  Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. , 2014, Journal of Alzheimer's disease : JAD.

[19]  G. Small,et al.  The merits of FDDNP-PET imaging in Alzheimer's disease. , 2011, Journal of Alzheimer's disease : JAD.

[20]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[21]  J. Trojanowski,et al.  Neurodegenerative tauopathies. , 2001, Annual review of neuroscience.